tbuckley/cabot-search huggingface dataset:
Abstract 575: Brain delivery of clinically suitable nanobioconjugates to inhibit glioblastoma growth through extracellular matrix-immune cell crosstalk
Authors: Alexander V. Ljubimov, Rameshwar Patil, Hui Ding, Liron Israel, Eggehard Holler, Julia Y. Ljubimova, Tao Sun, Keith L. Black
Journal: Cancer Research (2023)

Abstract Introduction: Tumor growth, invasion, and escape from immune surveillance largely depend on cancer microenvironment. Laminins are trimeric proteins and essential components of glioblastoma (GBM) microenvironment/extracellular matrix (ECM). In brain glioma samples from 230 patients, we found a correlation between the overexpression of tumor ECM protein laminin-411 (α4β1γ1) and faster tumor recurrence with shorter patient survival. Laminin-411 is produced by endothelial cells, neutrophils, monocytes, platelets, lymphocytes, and glioma cells and can modulate the immune system. Novel nanotechnology approach to block trimeric laminin-411 and activate of brain local immune system with brain delivery of PD-1 checkpoint inhibitor was developed for future translational application. Methods: Nanobioconjugates (NBC) based on poly (β-L-malic acid, P), were synthesized, characterized and used to intravenously treat mice with intracranial syngeneic GL261 or CT-2A GBM. The lead NBCs P/PEG/LLL(40%)/AON(α4β1)(2.0%)/AP-2(2%) and P/PEG/LLL(40%)/AP-2(2%)/αPD-1(0.2%) contained antisense to laminin-411 α4 and β1 chains, or αPD-1 antibody as well as trileucine (LLL) peptide for endosomal escape and AP-2 peptide for BBB crossing and tumor cell targeting. CRISPR/Cas9 constructs were used to knockdown α4 and β1 laminin chains in GBM ex vivo. Flow cytometry and RNA-seq analyses were performed to evaluate treatment. Results: Laminin-411 depletion with CRISPR/Cas9 and multifunctional NBC in vivo treatment equally suppressed GBM growth and significantly prolonged animal survival. The brain privileged immune system was activated upon treatment with a significant increase of CD3+, CD8+ T cells, NK, IFNγ+ NK cells, and M1 macrophages. RNA-sec analyses after treatment with a combination of NBC suppressing laminin-411 and checkpoint PD-1 showed enhanced anti-tumor effect with upregulation of genes coding for apoptotic Caspase 3 and IFNγ, and reduction of proliferation markers EGFR, c-Myc and Ki-67. Conclusion: Study describes novel GBM treatment strategy via NBCs crossing blood-brain barrier and targeting critical ECM and immune components of tumor microenvironment largely independent of heterogeneous genetic mutations in glioblastoma. Citation Format: Alexander V. Ljubimov, Rameshwar Patil, Hui Ding, Liron Israel, Eggehard Holler, Julia Y. Ljubimova, Tao Sun, Keith L. Black. Brain delivery of clinically suitable nanobioconjugates to inhibit glioblastoma growth through extracellular matrix-immune cell crosstalk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 575.
Abstract 6051: Dissecting unique metabolic vulnerabilities in triple-negative breast cancer metastasis
Authors: Divya Ramchandani, Liron Yoffe, Arshdeep Singh, Linda Vahdat, Vivek Mittal
Journal: Cancer Research (2023)

Abstract Introduction. Triple-negative breast cancer (TNBC) exhibits the worst outcome due to an aggressive clinical course, high rates of metastasis, and therapeutic resistance. Lack of effective FDA approved anti-metastatic targeted therapies has generated an unmet medical need for developing effective novel treatments. Targeting metastatic seeding and colonization remains a therapeutic challenge. Only recently, attention has been drawn to the idea that cancer cells selectively and dynamically adapt their metabolism along the changing microenvironments of the metastatic cascade. However, the precise nature of the metabolic reprograming in vivo is poorly understood and constitutes a major barrier in formulating a rationally designed therapeutic approach. Using a genetic lineage tracing approach, we identified a discrete subpopulation of highly metastatic SOX2/OCT4+ cells within primary tumors that exhibit enhanced invasion and metastasis, increased self-renewal, higher chromosomal instability, and marked resistance to chemotherapy. We posited that this lineage tracing system may allow assessment of precise metabolic alterations as a function of tumor progression directly in vivo. Methods and data. Transcriptomic analysis of sorted cellular fractions from progressing primary TNBC tumor identified metabolic heterogeneities between metastatic SOX2/OCT4+ and the SOX2/OCT4- counterparts. SOX2/OCT4+ metastatic cells exhibited elevated levels of mitochondrial respiration (OXPHOS) and fatty acid (FA) metabolism; a finding supported by proteomic analysis. Using a combination of CRISPR knockout of key pathway genes, seahorse metabolic flux analysis, metabolomics, and stable isotope tracing, we provide evidence for increased dependence of the metastatic SOX2/OCT4+ population on these unique metabolic adaptions. Importantly, we have identified upstream regulators of these pathways and demonstrate impact of both genetic and pharmacological inhibition of the metabolic regulatory networks on metastasis in vivo. Conclusion. By identifying metabolic adaptations unique to the metastatic compartment of the primary tumor, we provide evidence for using clinical grade pharmacological inhibitors including metformin, tetrathiomolybdate and FA pathway inhibitors like TVB-2640 and BMS-303141, as an anti-metastatic approach in TNBC. This knowledge of metabolic remodeling could therefore be employed as a next-generation therapeutic approach for high-risk TNBC patients. Citation Format: Divya Ramchandani, Liron Yoffe, Arshdeep Singh, Linda Vahdat, Vivek Mittal. Dissecting unique metabolic vulnerabilities in triple-negative breast cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6051.
Abstract 1323: Peristalsis based modulation of colorectal cancer cells leads to changes in stemness and invasiveness in an organ on chip model
Authors: Curran A. Shah, Carly Strelez, Yonatan Amzaleg, Einar B. Gunnarsson, Jasmine Foo, Min Yu, Shannon M. Mumenthaler
Journal: Cancer Research (2023)

Abstract Colorectal cancer (CRC) remains one of the deadliest cancers worldwide due to poor outcomes upon metastatic spread. Given the drastic impact on mortality, a better understanding of the CRC metastatic process could yield significant improvements to overall survival. Here, we investigate the influences of biomechanical forces on early metastatic spread (i.e., tumor cell intravasation events) in an organ-on-chip (OOC) model. Our microfluidic CRC OOC model consists of two channels separated by a porous membrane: a top channel representing normal and cancerous colon epithelial tissue, and a bottom channel consisting of endothelial cells in a tube-like structure representing the vasculature. Vacuum channels flank the sides of the model to apply forces in a cyclic manner to mimic peristalsis-like motions and provide further in vivo resemblance. In our prior work, we demonstrated that peristaltic forces promoted tumor cell invasion within the CRC OOC. Specifically using on-chip confocal imaging, we revealed that cyclic strain leads to an increase in the number of tumor cells capable of intravasating from the epithelial channel into the vascular channel. Additionally, we showed dynamic sensitivity of tumor cell invasion in response to intermittent stretching conditions, leading us to hypothesize mechanical stress-induced phenotypic switching. Therefore, using single-cell RNA sequencing, we investigated gene expression changes of tumor cells in the presence or absence of peristaltic forces and found alterations in stemness, adhesion and metabolism-related genes. Using median fluorescence intensity (MFI) from flow cytometry data, we have revealed differences in stem-like properties (e.g., CD44, CD133, LGR5) of tumor cells with and without the influence of peristaltic forces both prior to and after intravasation. Additionally, effluent-based analysis of the OOC has shown cytokine and metabolism changes due to peristaltic forces. Ongoing work involves using flow cytometry to further quantify changes in adhesion and metabolism as well further validation in patient derived organoids-on-a-chip. Taken together, OOCs provide a physiologically relevant model to study early CRC intravasation events, revealing phenotypic changes in response to mechanical stimuli that influence tumor cell stemness and invasiveness. Citation Format: Curran A. Shah, Carly Strelez, Yonatan Amzaleg, Einar B. Gunnarsson, Jasmine Foo, Min Yu, Shannon M. Mumenthaler. Peristalsis based modulation of colorectal cancer cells leads to changes in stemness and invasiveness in an organ on chip model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1323.
Abstract 3782: Targeting cancer cells using folate conjugated to a fully modified version of miR-34a (FolamiR-34a) to produce enhanced and sustained anti-tumor activity
Authors: Shreyas Ganesan Iyer, Ahmed M. Abdelaal, Ikjot Singh Sohal, Sudarsan R. Kasireddy, Andrea L. Kasinski
Journal: Cancer Research (2023)

Abstract Due to the pleiotropic nature of miR-34a, including its ability to downregulate multiple genes that drive resistance to currently used anti-cancer therapies, we hypothesize that the best use of miR-34a in a clinical setting would be in combination with standard-of-care treatments. For in vivo use, such a molecule would necessitate the following: i) a stabilized version of miR-34a that can withstand the harsh environment in circulation and intracellular nucleases, and ii) a robust, specific, and safe delivery vehicle. With regard to stability, we successfully generated the first fully modified version of miR-34a. This new chemically modified molecule is over 400-fold more stable than the previously used partially modified version and induces enhanced and sustained target gene repression. To assess in vivo activity of fully modified miR-34a requires a suitable delivery vehicle. Indeed, while various approaches have been used to restore miR-34a in tumors, clinically relevant mechanisms for delivery of miR-34a have been a challenge due to poor tumor uptake, unfavorable bioavailability, and unwanted toxicity. Previously, we determined that a partially modified version of miR-34a can be delivered specifically and robustly to cancer cells in a targeted, vehicle-free manner through direct conjugation to folate, a ligand of the high-affinity folate receptors. Thus, we conjugated our fully modified miR-34a (FM-miR-34a) to folate generating FM-FolamiR-34a. Following in vivo delivery of FM-FolamiR-34a to mice with breast cancer xenografts we observed enhanced and sustained target gene repression, in comparison to our first-generation partially modified folate-miR-34a conjugate (FolamiR). Critical miR-34a target genes involved in promoting resistance, including MET, AXL, and CD44 were downregulated over 90% for at least 120 hours following a single 1.5 nmol dose of FM-FolamiR-34a. Our final objective is to evaluate FM-FolamiR-34a in combination with standard-of-care agents in vivo. Citation Format: Shreyas Ganesan Iyer, Ahmed M. Abdelaal, Ikjot Singh Sohal, Sudarsan R. Kasireddy, Andrea L. Kasinski. Targeting cancer cells using folate conjugated to a fully modified version of miR-34a (FolamiR-34a) to produce enhanced and sustained anti-tumor activity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3782.
Abstract 5202: NCG-M humanized mice: an excellent model for human immune reconstitution of myeloid lineages
Authors: Huiyi Wang, Jialu Fan, Shiying Guo, Mingkun Zhang, Shuai Li, Santi Suryani Chen, Zhiying Li, Mark Wade Moore, Jing Zhao, Xiang Gao, Cunxiang Ju
Journal: Cancer Research (2023)

Abstract Severe immunodeficient mice engrafted with human hematopoietic stem cells (HSC) have been extensively used in immuno-oncology related studies to evaluate the efficacy of cancer therapies. However, because of species differences, murine cytokines provide limited support to human immune cells, thus immunodeficient mice have limited engraftment of human immune cells. Increasing evidence has shown that myeloid cells, especially macrophages and dendritic cells, are critical for the induction of anti-tumor immunity. We developed a mouse model, NCG-M, that can support human T, B, NK and myeloid cells such that in vivo evaluation of agents that require the interplay between these immune cells can be examined. This model was genetically engineered on the severe immunodeficient strain NCG and can produce human granulocyte/macrophage colony stimulating factor 2 (GM-CSF, also known as CSF2), interleukin-3 (IL-3) and stem cell factor (SCF, also known as KITLG). Upon human CD34+ HSC cell engraftment, increased myeloid lineage cells, such as granulocytes, monocytes, neutrophils, macrophages, and dendritic cells, were observed in the NCG-M cohort compared to NCG mice. The NCG-M mouse also supports the development of human T cells, and preliminary data showed increased B and NK cells. The NCG-M is an appropriate mouse model for studying the efficacy of therapeutic agents that require human T cells and myeloid cells. Citation Format: Huiyi Wang, Jialu Fan, Shiying Guo, Mingkun Zhang, Shuai Li, Santi Suryani Chen, Zhiying Li, Mark Wade Moore, Jing Zhao, Xiang Gao, Cunxiang Ju. NCG-M humanized mice: an excellent model for human immune reconstitution of myeloid lineages. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5202.
Abstract 2534: Targeting defective necroptosis in colorectal cancer to overcome therapeutic resistance
Authors: Kaylee Ermine, Dongshi Chen, Xinyan Lu, Jian Yu, Lin Zhang
Journal: Cancer Research (2023)

Abstract Colorectal cancer (CRC) is a leading cause of cancer related deaths in the United States. CRC patients are often treated with the chemotherapeutic drug 5-fluorouracil (5-FU), but resistance often occurs. It is well-established that 5-FU induces apoptosis in cancer cells, but apoptosis inhibition does not block the anticancer effect of 5-FU, suggesting a role of non-apoptotic cell death. Necroptosis is a regulated form of necrosis controlled by Receptor-Interacting Protein kinase 1 (RIP1), RIP3, and Mixed Lineage Kinase domain-Like (MLKL), and its role in anticancer therapy remains unclear. TCGA RNAseq data show that RIP3 is significantly downregulated in primary CRC tumors, which is correlated with worse outcomes. RIP3 downregulation also occurs in established CRC cell lines and is associated with decreased 5-FU sensitivity. Therefore, we hypothesize that necroptosis may play a critical role in anticancer therapy and that restoring defective necroptosis may enhance therapeutic sensitivity. Our studies show that RIP3-expressing (RIP3+) CRC cells undergo both apoptosis and necroptosis in response to 5-FU. As expected, knock-out of RIP3 in RIP3+ CRC cells resulted in decreased 5-FU sensitivity, as well as abrogated necroptosis induction. Additionally, stable restoration of RIP3 in RIP3-silenced (RIP3-) CRC cells appeared to enhance 5-FU response, under conditions where apoptosis was inhibited. Furthermore, we explored alternative ways to induce necroptosis in RIP3-silenced cells. Together, our results suggest that necroptosis plays an important role in 5-FU-induced cell death in CRC. These results provide novel insights into the role of necroptosis in anticancer therapy in CRC, which could be used for development of improved therapies and personalized medicine based on RIP3 status. Citation Format: Kaylee Ermine, Dongshi Chen, Xinyan Lu, Jian Yu, Lin Zhang. Targeting defective necroptosis in colorectal cancer to overcome therapeutic resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2534.
Abstract 1501: Epigenetic dedifferentiation as a therapeutic strategy in adrenal cancer
Authors: Dipika R. Mohan, Kleiton S. Borges, Isabella Finco, Christopher R. LaPensee, Juilee Rege, Donald W. Little, Tobias Else, Madson Q. Almeida, Derek Dang, James Haggerty-Skeans, Ana Claudia Latronico, Berenice B. Mendonca, Richard J. Auchus, William E. Rainey, Suely K. Marie, Thomas J. Giordano, Sriram Venneti, Maria Candida B. Fragoso, David T. Breault, Antonio M. Lerario, Gary D. Hammer
Journal: Cancer Research (2023)

Abstract Adrenocortical carcinoma (ACC) is a rare cancer of the adrenal cortex without curative medical therapies. CIMP-high is an aggressive ACC molecular subtype defined by global CpG island hypermethylation with paradoxical activation of adrenal differentiation (driven by master transcription factor SF1) and stemness (driven by β-catenin). We show DNA hypermethylation redistributes histone methyltransferase EZH2 and its mark, H3K27me3. EZH2 inhibition remains lethal to CIMP-high ACC cells, erasing transcriptional programs without altering DNA methylation. We reconcile this phenomenon by discovery of two nuclear complexes, SF1/β-catenin and EZH2/β-catenin, present in physiology and persistent through advanced ACC. We find SF1/β-catenin is a chromatin-bound complex that controls the ACC super-enhancer landscape, while EZH2/β-catenin is restricted to off-chromatin pools. EZH2 inhibition purges SF1/β-catenin from chromatin, sparing EZH2/β-catenin, inducing dedifferentiation and restraining ACC growth in vitro and in vivo. Our studies illustrate how cell-of-origin programs dictate cancer evolution, exposing differentiation as an therapeutic vulnerability. Citation Format: Dipika R. Mohan, Kleiton S. Borges, Isabella Finco, Christopher R. LaPensee, Juilee Rege, Donald W. Little, Tobias Else, Madson Q. Almeida, Derek Dang, James Haggerty-Skeans, Ana Claudia Latronico, Berenice B. Mendonca, Richard J. Auchus, William E. Rainey, Suely K. Marie, Thomas J. Giordano, Sriram Venneti, Maria Candida B. Fragoso, David T. Breault, Antonio M. Lerario, Gary D. Hammer. Epigenetic dedifferentiation as a therapeutic strategy in adrenal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1501.
Abstract 4990: Dual inhibitor of ACVR1 and MEK 1/2 E6201 and PI3K/mTOR inhibitor paxalisib synergistically inhibit cell growth in DMG
Authors: Hyuk Jean Kwon, Abigail Tindall, Charles Eberhart, Jeffrey Rubens, Eric Raabe
Journal: Cancer Research (2023)

Abstract Diffuse midline glioma (DMG) is an aggressive pediatric glioma with no curative treatment options. Mutation in MAPK pathway is common in many DMG tumors, however, has not been largely explored before. E6201 is a dual inhibitor of ACVR1 and MEK 1/2. It is currently in a phase 1 clinical trial for BRAF/MEK mutant melanoma. E6201 achieves higher levels in brain compared to other MEK inhibitors, suggesting it might be a promising therapeutic option for DMG. Previously, E6201 was effective in DMG cell lines with ACVR1 mutation, such as HSJD007. We have evaluated the effect of E6201 in two MAP kinase pathway activated, novel DMG cell lines, DIPG2JA and JHH-DIPG17. DIPG2JA has a KRAS mutation, leading to upregulation of MAPK pathway, and JHH-DIPG17 has two NF1 alterations predicted to disrupt this tumor suppressor, resulting in activation of MAPK pathway. Treatment of DIPG2JA with E6201 identified an IC50 of 44 nM, which is comparable to an IC50 of 71nM in the ACVR1 mutant DMG HSJD007. E6201 suppressed phospho—ERK and induced apoptosis as measured by cPARP western blot in DMG cells. Evaluation of cell viability by CellTiterBlue viability assay demonstrated that E6201 suppressed DMG growth between 0.05uM to 1uM concentrations. (DIPG2JA p=0.0004, JHH-DIPG17 p&amp;lt;0.0001 by t-test compared to control). Compensatory upregulation of mTOR pathway is often associated with downregulation of MAPK pathway, and we hypothesized that E6201 will synergize with a PI3K/mTOR inhibitor to induce DMG cell death. We selected the brain-penetrant PI3K/mTOR inhibitor paxalisib, because this drug is currently being tested in early phase clinical trials for DMG. Through CellTiterBlue cell viability assay, we showed that E6201 synergizes with paxalisib to inhibit cell growth. The ZIP synergy scores were 13.1 for HSJD007 and 12.7 for DIPG2JA according to the SynergyFinder program, suggesting synergistic interaction between E6201 and paxalisib. In vitro experiments for further evaluation of the combination treatment of E6201 and paxalisib are underway and in vivo studies are pending. From our data, E6201 as a single agent is a promising therapeutic option for DMG. With further evaluation of combination of E6201 and paxalisib, we believe that combination therapy will be an even more effective treatment option for DMG. Citation Format: Hyuk Jean Kwon, Abigail Tindall, Charles Eberhart, Jeffrey Rubens, Eric Raabe. Dual inhibitor of ACVR1 and MEK 1/2 E6201 and PI3K/mTOR inhibitor paxalisib synergistically inhibit cell growth in DMG. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4990.
Abstract 6152: Exploiting ferroptosis in mutant BAP1 uveal melanoma
Authors: Camille J. Cunanan
Journal: Cancer Research (2023)

Abstract Uveal melanoma (UM) arises from melanocytes of the uveal tract in the eye and is the most common intraocular malignancy in adults. Primary UM lesions often harbor mutations in G-proteins, GNAQ or GNA11, and are successfully treated by radiotherapy or enucleation. However, 50% of patients develop metastases. Of these metastatic UM (MUM) patients, 80%develop metastases to the liver, an effect strongly correlated with the loss of function of BAP1,a nuclear deubiquitinase. BAP1-mutant MUMs are less responsive to conventional treatments, such as chemotherapy and immune checkpoint inhibitors, with 50% of these patients having an overall survival of only 1 year. We propose that the unique metabolic intermediates found in liver microenvironment may dictate MUM tropism, aggressiveness, and poor therapeutic response. Here, using a combination of in vitro and ex vivo liver slice cultures, we found that the liver microenvironment induces gene expression alterations consistent with limiting the toxicity of reactive oxygen species (ROS). Importantly, we note that mutant BAP1 UM displayed improved ROS detoxification compared to its wildtype counterparts. Furthermore, publicly available datasets suggest patients with mutant BAP1 UM, the subset of patients with liver metastases, have corresponding ROS detoxification gene expression patterns. These findings suggest that the liver microenvironment and BAP1 loss directs MUM to mitigate ROS-associated toxicity. This compensatory mechanism may be therapeutically exploited and pair well as a combination treatment with the recently approved bispecific agent, Tebentafusp, to selectively target liver MUM. Citation Format: Camille J. Cunanan. Exploiting ferroptosis in mutant BAP1 uveal melanoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6152.